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Wnt signaling pathway is critically important in stem cell biology, both in homeostatic maintenance and regeneration of tissues and organs. Aberrant activation of this pathway has been described as a key player in the development of a wide array of tumor types, via affecting the behavior of Cancer Stem Cells (CSCs). CSCs are believed to be responsible for disease relapse, as they possess drug-resistance properties.The development of new therapeutic drugs targeting this pathway topromise new hope to eliminate CSCs and achieve cancer eradication. We review the Wnt signaling pathway, the relationship between this pathway and CSC term and recent therapeutic approaches to target this pathway and their clinical applications, Wnt sinyal yolağı kök hücre biyolojisinde, doku ve organ rejenerasyonunda ve homeostatik devamlılığın sağlanmasında kritik bir öneme sahiptir. Bu yolağın anormal aktivasyonunun pek çok tümör tipinin gelişiminde anahtar bir rol oynadığı ve bu durumun kanser kök hücrelerin (KKH, cancer stem cell=CSC) davranışını etkilediği bilinmektedir. KKH’ler ilaca direnç gösterebilme özelliğinden dolayı hastalıkların nüks etmesinin temel nedeni olduğu düşünülmektedir. Wnt sinyal yolağını hedef alan yeni terapötik ilaçların keşfedilmesi, KKH’lerin elimine edilmesine ve kanserin yok edilmesine yönelik yeni umutlar vaat etmektedir. Bu derleme de Wnt sinyal yolağı, bu yolağın kanser kök hücre kavramı ile ilişkisi ve klinik uygulamalarını hedef alan yakın zamandaki terapötik yaklaşımlar tartışılmıştır

It is an effective antioxidant molecule that exhibits free radical scavenging activity and it enhances antioxidant status in rats and exhibited anticancer properties. It has been shown that α-Lipoic acid is a very effective molecule against type 2 diabetes, atherosclerosis, inflammatory skin diseases, reperfusion arrhythmias and Parkinson’s disease and serves apoptotic action in different cancer cells. These molecules can display important roles in treatment of colon cancer. In this study, we examined the synergetic effects of α-lipoic acid and L-carnitine on HCT 116 +/+ and HCT 116 -/- colon cancer cell line. For this purpose, HCT 116 +/+ and -/- colon cancer cells were treated with L-carnitine and α-Lipoic acid for 24 hours and MTT assay and caspase 3 enzyme activity assay was conducted. α -Lipoic acid and L-carnitine alone or in combination decreased cell viability in HCT 116 +/+ and /- colon cancer cells and exhibited synergetic effect on the cell viability. Further studies must be conducted to find out the mechanism of their effects in cancer therapy, L-karnitin, uzun zincirli yağ asitlerinin mitokondri matriksine transportunda yer alarak, lipid metabolizmasında önemli görevlere sahip olan bir molekül olmasının yanı sıra, serbest radikal temizleyici aktivite gösterir ve antikanser özellikler sergiler. α-Lipoik asitin, tip2 diyabet, ateroskleroz, inflamatuar deri hastalıkları ve Parkinson hastalığına karşı oldukça etkili bir molekül olduğu gösterilmiştir ve farklı kanser hücrelerinde apoptotik etkiler gösterdiği bilinmektedir. Bu çalışmada, α-Lipoik asit ve L-Karnitin’in, HCT 116 +/+ ve HCT 116 -/- kolon kanseri hücre serilerindeki sinerjetik etkileri araştırılmıştır. Bu amaçla, HCT 116 +/+ ve -/- kolon kanseri hücreleri, L-karnitin ve α-Lipoik asit ile 24 saat muamele edildikten sonra, MTT testi ve kaspaz 3-enzim aktivitesi ile hücre canlılığı ve kaspaz-3 enzim aktivitesi üzerindeki etkileri incelenmiştir. Bu çalışmada, α-Lipoik asit ve Lkarnitin’in, kombinasyon halinde verildiklerinde sinerjetik etkiler sergileyerek, HCT 116 +/+ ve -/- kolon kanseri hücrelerinin canlılığını azalttıkları ve kaspaz-3 enzim aktivitesini artırdıkları görülmüştür. L-karnitin ve α-Lipoik asitin kanser terapisindeki sinerjetik etkilerinin mekanizmasını açığa çıkarmak için daha ileri çalışmalar yapılmalıdır

Acute myeloid leukemia is a type of clonal hematopoietic stem cell disorder displaying different genetic abnormalities. The critical balance between the self-renewal and differentiation of leukemia stem cells are regulated by various genes and signaling pathways that are regulated by these genes. Wnt/ β-catenin signaling pathway controls the self-renewal of hematopoietic stem cells by the regulation of β-catenin. Akirin-2 is an evolutionarily conserved nuclear protein which is thought to play important roles in immunity, NFκB and Wnt/β-catenin signaling pathways. In this study, expression of Akirin-2 gene was investigated in the CD34+ hematopoietic stem cells of patients with high β-catenin gene expression. Our results showed that the expression level of Akirin-2 gene was significantly higher in CD34+ hematopoietic stem cells of patients compared to healthy subjects and Akirin-2 gene could have an important role in AML pathogenesis, Akut miyeloid lösemi (AML), farklı genetik anomaliler gösteren bir grup klonal hematopoetik kök hücre bozukluğudur. Lösemik kök hücrelerin kendini yenileme ve farklılaşmaları arasındaki hassas dengeyi, çeşitli genler ve bu genlerin düzenlediği sinyal yolakları kontrol etmektedir. Wnt/β-katenin sinyal yolağı, β-kateninin regülasyonu aracılığıyla hematopoetik kök hücrelerin kendilerini yenilemelerini kontrol etmektedir. Akirin2 proteini ise, immünite, NFκB ve Wnt/β-katenin sinyal yolaklarında çok önemli rolleri olduğu düşünülen yüksek derecede korunmuşluk gösteren bir proteindir. Bu çalışmada β-katenin gen ekspresyonu yüksek olan AML hastalarının CD34+ hematopoetik kök hücrelerinde Akirin2 geninin ifadesi araştırılmıştır. Sonuç olarak Akirin2 gen ifadesinin AML hastalarının CD34+ hematopoetik kök hücrelerinde sağlıklı bireylere göre anlamlı derecede artmış olduğu tespit edilmiş ve Akirin2 geninin AML patogenezinde önemli rollerinin olabileceğine dair ilk veriler elde edilmiştir

Aim:Apoptosis is a genetically programmed cell death mechanism which plays important roles in normal physiology such as tissue homeostasis regulation and pathophsiology of various diseases. iNOS enzyme activation and nitric oxide synthesis in various cell types as a defense mechanism against microbial and viral pathogens plays an important role in inflammatory and immune pathologies such as atherosclerosis, rheumatoid arthritis, diabetes, septic shock, multiple sclerosis and highly uncontrolled production of nitric oxide leads to cell death. Recently, glucosamine which is acclaimed to be beneficial for inflammatory disorders such as osteoarthritis is widely used clinically. There is limited information regarding the effect mechanisms of glucosamine on apoptosis of mainly immune cells, macrophages. In this study, effects of different concentrations of glucosamine were tested on LPS/IFNγ activated RAW 264.7 macrophages.Materials and methods:RAW 264.7 macrophage cell line was treated with or without glucosamine before LPS/IFNγ stimulation. Nitrite levels, cell viability, caspase-3 activity, mitochondria membrane potential and flow cytometric analysis with Annexin V-PI cell staining was performed.Results and discussion:Glucosamine inhibited nitrite levels, increased mitochondrial membrane potential, decreased caspase-3 enzyme activity significantly (p

Acute Myeloblastic Leukemia (AML) is a disease characterized with disruption of normal hematopoietic growth and differentiation and accumulation of numerous abnormal unmatured myeloid cells. Epigenetic mechanisms, in particular DNA methylation and histon modifications, play a major role in the modulation of gene activity in cancer and cause acute leukemias. Epigenetic changes can reverse pharmacologically with demethylating agents which are in use as targeted therapy of hematological malignancies. Methylprednisolone(MP) has been used with short course and high dose for treating newly diagnosed children with AML. Methylprednisolone induces differentiation of myeloid leukemia cells to granulocytes and macrophages and induces apoptosis of myleoid leukemia cells. First, MTT test is performed for evaluating how different MP doses effect cell cytotoxicity in time dependent manner. Viability decreased with increasing MP doses both 24. And 48. hours. For these doses, apoptosis and differentiation determinations were done with flow cytometry analysis. Following this step, the high and effective dose for HL60 cells established as 5x10-3. For this dose, DNA isolation wass done. After isolation, methylation specific PCR analysis was performed for p15, ER, CDX2 and Bcl-2 genes. According to results, while p15 and Bcl-2 gene promoters are unmethylated, ER and CDX2 gene promoters are methylated. In conclusion, the methylation profiles of p15, CDX2, ER and Bcl-2 do not change after MP treatment.MP has apoptotic effect and differentiates myeloid blast cells but it does not effect DNA methylation. It is the first in the literature that demonstrates if methylprednisolone shows its effect with epigenetic pathway. In conclusion HL-60 cell line shows that MP doesn’t effect DNA methylation, Akut Myeloid Lösemi (AML), erken hematopoetik kök hücrelerde bir dizi genetik değişiklik sonucunda normal büyüme ve farklılaşmanın bozulması, kemik iliği ve periferik kanda çok sayıda anormal olgunlaşmamış myeloid hücrenin birikimi ile karakterize olan bir hastalıktır. Son yıllarda, löseminin oluşum sürecinde DNA metilasyonundaki ve histon modifikasyonlarındaki değişikliklerin etkili olduğu konusunda çalışmalar yapılmış ve AML ve demetile edici ajanlar hematolojik hastalıkların tedavisi için hedef olarak belirlenmiştir. Yüksek doz metilprednizolon yeni tanı almış pediatrik AML hastalarının tedavisinde kısa süreli uygulanmakta ve başarılı sonuçlar alınmaktadır. Sentetik bir glukokortikoid olan metilprednizolonun (MP) yüksek dozda, myeloid lösemi hücrelerinin granülositlere ve makrofajlara farklılaşmasını ve myeloid lösemi hücrelerde apoptozisi indüklediğine dair çalışmalar literatürde bulunmaktadır. Bizim çalışmamızda, AML hücre serisinde metilprednizolonun farklı dozlarda hücreler üzerindeki sitotoksisite düzeylerini saptamak amacıyla MTT yöntemi kullanıldı. MTT testi sonucu canlılığın anlamlı derecede azaldığı dozlarda 24. ve 48. saatlerde apoptozis ve farklılaşma analizleri akım sitometri ile yapıldı. Etken dozun 5x10-3 olarak bulundu ve bu etken dozun uygulandığı HL-60 hücreleri ve kontrol grubu hücrelerinden DNA izolasyonu yapılarak metilasyon analizlerine devam edildi. AML’de sıklıkla metile olduğu bildirilen p15, ER ve anormal ekspresyonu görülen BCL-2 ve CDX2 genlerinin HL-60 AML hücre serisinde steroid tedavisi öncesi ve sonrası metilasyonuna bakılarak, metilprednizolonun etkisini, epigenetik yolaktan gösterip göstermediğini araştırıldı. P15 geni promotoru ve BCL-2 geni promotoru metile bulunmamıştır. ER geni promotoru ve CDX2 geni promotoru ise metile bulunmuştur. MP uygulaması sonrası genlerin metilasyon profillerinde bir değişiklik saptanmamıştır. Çalışmamızda yüksek ve etken dozun hücreleri farklılaşmaya ve apoptozise götürdüğü ancak bunu epigenetik yolak mekanizmalarından biri olan DNA metilasyonu üzerinden yapmadığı saptandı

To investigate the possible effects of aqueous garlic extract on the oxidant/antioxidant status and apoptosis in 32D (wild type mouse myeloid cell = normal) and 32Dp210 (BCR-ABL fusion gene (+) mouse myeloid cell = Chronic Myelocytic Leukemia cells) cell lines. Materials and methods: Aqueous garlic extract (10% w/v) was added into the cell line media with 2 different final concentrations (0.4% and 1%). At 0 h and at 24, 48, and 72 h later, the oxidant (malondialdehyde (MDA) level, and xanthine oxidase (XO) enzyme activity) and antioxidant (superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) enzyme activities) parameters were measured in the cell lines. Results: It was observed that the garlic extract caused no change in the XO and antioxidant enzyme activities, but it increased the MDA level in the 32D cell line. However, significant increases were found in the MDA level, XO, and antioxidant enzyme activities in the 32Dp210 cell line treated by the garlic extract. Additionally, it was shown that garlic extract had antiproliferative and apoptotic effects on both cell lines. The most effective apoptotic dose was found to be 0.4% (w/v), and at this concentration the death risk of the 32Dp210 cell line was calculated at 2.08 times higher than that of the 32D cell line. Conclusion: It has been suggested that garlic directly causes oxidant stress in the 32D cell line owing to its own oxidant ingredients, and that the oxidant stress created by garlic in the 32Dp210 cell line might occur through increased XO activity and/or its oxidant ingredients. Additionally, antioxidant enzyme activities were found to increase in the 32Dp210 cell line; it would seem that this compensatory change could not prevent the oxidant stress created. We think that the oxidant potential of garlic extract might play a part in its possible anticancer potential, previously supposed by several investigators.

Glutathione S-transferases (GSTs) are phase II enzymes that detoxify hazardous xenobiotics including carcinogens. Inter-individual variations in GSTM1 and GSTT1 loci have been associated with several types of cancer, including leukemias. In this study, we investigated the possible association between GSTM1 and GSTT1 polymorphisms and susceptibility to chronic myeloid leukemia (CML) in a Turkish population. In a case-control study, 106 CML patients and 190 healthy controls were evaluated for GSTM1 and GSTT1 polymorphisms. GSTM1 null (GSTM1(-)) genotype frequencies in CML cases and controls were 45.3% and 42.6%, respectively. GSTT1 null (GSTT1(-)) genotype frequencies were 44.3% and 18.4%, respectively. The frequency of the GSTT1(-) genotype among CML patients was significantly higher than in controls [odds ratio (OR) 3.53, 95% confidence interval (CI) 2.08-6.00; P0.0001]. Individuals with the GSTM1(-) genotype did not have increased risk of CML [OR: 1.11; 95% CI: 0.69-1.80; P = 0.714]. The combined GSTM1(-)/GSTT1(-) genotype was significantly associated with risk of CML compared to the GSTM1(+) /GSTT1(+) genotype which was most frequent in both cases and controls [OR: 9.47; 95% CI: 3.61-24.87]. Similar findings have only been obtained in Turkish and Indian populations but not elsewhere. The GSTM1(+) /GSTT1(-) genotype was associated with a 2.5-fold increased risk compared with the GSTM1(-)/GSTT1(+) genotype, the second most frequent genotype (OR; 2.46; 95% CI: 1.17, 5.20), suggesting a complex interaction between GSTM1 and GSTT1. Our results indicate an association between the GSTT1(-) genotype, either alone or in combination with GSTM1(-) genotype, and risk of CML, suggesting a possible interaction between GSTM1 and GSTT1. These findings, which are possibly restricted to Turkey and India, warrant further research.